The trihalogenated corticosteroid halobetasol propionate of the formula
also known as ulobetasol propionate is (6α, 9α, 11β, 16β, 17α)-21-Chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)pregna-1,4-diene-3,20-dione.
Halobetasol propionate has been described in U.S. Pat. No. 4,619,921 as a new topical polyhalogenated corticosteroid, presenting topical anti-inflammatory activity, whilst having low systemic activity. Halobetasol propionate is marketed in the U.S. as Ultravate® cream and Ultravate® ointment. It is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
The search for new crystalline forms is relevant to the pharmaceutical sciences, since different crystalline forms of the same drug can possess different dissolution profile, pharmacokinetic profile and stability properties. The discovery of a new crystalline form of a drug provides an opportunity to improve its performance—it broadens the repertoire of materials that a formulation scientist has available for designing, for example, a specific release profile.
The Ultravate products contain only one, yet uncharacterized, crystalline form. The efficacy and safety of other crystalline forms was heretofore unknown. The new crystalline forms are obtained economically, in very good yields via convenient processes and exhibit good stability. Most of the solvents used for their preparation (unlike those described in U.S. Pat. No. 4,619,921) are safe and allow easy handling.
We have now surprisingly found that the new crystalline forms can be formulated in stable topical pharmaceutical compositions with similar or better efficacy than the marketed Ultravate® products.
In addition, the new crystalline forms exhibited excellent solubility and handling properties, allowing for a convenient pharmaceutical manufacturing process. They can be easily suspended or solubilized in the usual pharmaceutical ingredients.
Halobetasol propionate is described in the Merck Index and in U.S. Pat. No. 4,619,921 as being crystallized from methylene chloride/ether and having a melting point of 220–221° C. The exact proportions of the two solvents were not given. Precise characterization of the above mentioned crystalline form of halobetasol propionate, using methods well known to those skilled in the art (powder X-ray diffraction, differential scanning calorimetry, infra-red spectroscopy, etc.) and the exact process for their preparation, is not given. There is no documented evidence that characterizes any crystalline form other than the melting point given in U.S. Pat. No. 4,619,921.
The present invention provides six new crystalline forms of halobetasol propionate and processes for preparing them and stable topical pharmaceutical compositions containing the above crystalline forms.